Processes for the preparation of compounds of formula (I): ##STR2## wherein n is 0, 1 or 2;
each R.sup.1 is independently halo or lower alkyl; PA0 R.sup.2 is nitro or --N(R.sup.3)R.sup.4 where PA0 each R.sup.1 is independently halo or lower alkyl; PA0 R.sup.2 is nitro or --N(R.sup.3)R.sup.4 where PA0 (1) reacting the compound of formula (B): ##STR4## with a compound of formula (D): ##STR5## wherein R.sup.9 is halo, tosylate or mesylate, in the presence of a strong acid selected from the group consisting of alkanesulfonic acids, arenesulfonic acids and Lewis acids, to yield a mixture of stereoisomers represented by the following formula (E): ##STR6## wherein R.sup.9 is halo, tosylate or mesylate; (2) dissolving the mixture of stereoisomers represented by formula (E), as defined above, in a suitable solvent and treating the resulting solution with about 0.5 to about 2.0 molar equivalents of concentrated nitric acid to yield a compound of formula (Eb): ##STR7## wherein R.sup.9 is halo, tosylate or mesylate, as a precipitate; (3) treating the mother liquor resulting from the preparation of the compound of formula (Eb) with a suitable base and allowing the resulting mixture to crystallize from a suitable solvent to yield a compound of formula (Ea): ##STR8## wherein R.sup.9 is halo, tosylate or mesylate; and (4) treating a compound of formula (Ea), as defined above, with a compound of formula (F): ##STR9## wherein n is 0, 1 or 2; PA0 each R.sup.1 is independently halo or lower alkyl; PA0 R.sup.2 is nitro or --N(R.sup.3)R.sup.4 where PA0 in the presence of base to yield a compound of formula (I), as defined above. PA0 (5) treating the compound of formula (Eb) so formed with a suitable base to yield a compound of formula (Ec): ##STR10## wherein R.sup.9 is halo, tosylate or mesylate; and (6) treating the compound of formula (Ec) so formed with a strong acid selected from the group consisting of alkanesulfonic acids, arenesulfonic acids and Lewis acids, to yield the mixture of stereoisomers represented by formula (E), as defined above in Step (1). PA0 (a) dissolving the mixture of stereoisomers represented by formula (E), as defined above, in a suitable solvent and treating the resulting solution with about 0.5 to about 2.0 molar equivalents of concentrated nitric acid to yield a compound of formula (Eb): ##STR14## wherein R.sup.9 is halo, tosylate or mesylate, as a precipitate; and (b) treating the mother liquor resulting from the preparation of the compound of formula (Eb) with a suitable base and then allowing the resulting mixture to crystallize from a suitable solvent to yield a compound of formula (Ea), as defined above. PA0 R.sup.2 is --N(R.sup.3)R.sup.4 where R.sup.3 is hydrogen and R.sup.4 is hydrogen or --C(Y)R.sup.5 where Y is oxygen and R.sup.5 is methyl, or a pharmaceutically acceptable salt thereof; PA0 (1) reacting the compound of formula (B): ##STR18## with a compound of formula (D): ##STR19## wherein R.sup.9 is tosylate, in the presence of methanesulfonic acid, to yield a mixture of stereoisomers represented by the following formula (E): ##STR20## wherein R.sup.9 is tosylate; (2) dissolving the mixture of stereoisomers represented by formula (E), as defined above, in a suitable solvent and treating the resulting solution with about 0.8 to about 1.0 molar equivalents of concentrated nitric acid to yield a compound of formula (Eb): ##STR21## wherein R.sup.9 is tosylate, as a precipitate; (3) treating the mother liquor resulting from the preparation of the compound of formula (Eb) with sodium hydroxide and then allowing the resulting mixture to crystallize from isopropanol to yield a compound of formula (Ea): ##STR22## wherein R.sup.9 is tosylate; (4) treating a compound of formula (Ea), as defined above, with a compound of formula (F): ##STR23## wherein n is 0; and PA0 R.sup.2 is --N(R.sup.3)R.sup.4 where R.sup.3 is hydrogen and R.sup.4 is hydrogen or --C(Y)R.sup.5 where Y is oxygen and R.sup.5 is methyl; PA0 in the presence of potassium carbonate to yield a compound of formula (I), as defined above. PA0 (a) dissolving the mixture of stereoisomers represented by formula (E), as defined above, in a suitable solvent and treating the resulting solution with about 0.8 to about 1.0 molar equivalents of concentrated nitric acid to yield a compound of formula (Eb): ##STR26## wherein R.sup.9 is tosylate as a precipitate; (b) treating the mother liquor resulting from the preparation of the compound of formula (Eb) with a suitable base and allowing the resulting mixture to crystallize from a suitable solvent to yield a compound of formula (Ea), as defined above.
R.sup.3 is hydrogen or lower alkyl; PA1 R.sup.4 is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R.sup.5 where Y is oxygen or sulfur and R.sup.5 is hydrogen, lower alkyl, lower alkoxy or --N(R.sup.6)R.sup.7 where R.sup.6 is hydrogen or lower alkyl and R.sup.7 is hydrogen, lower alkyl or lower alkoxycarbonyl; or PA1 R.sup.3 and R.sup.4 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by --C(O)R.sup.8 where R.sup.8 is hydrogen, lower alkyl, lower alkoxy or amino; PA1 R.sup.3 is hydrogen or lower alkyl; PA1 R.sup.4 is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R.sup.5 where Y is oxygen or sulfur and R.sup.5 is hydrogen, lower alkyl, lower alkoxy or --N(R.sup.6)R.sup.7 where R.sup.6 is hydrogen or lower alkyl and R.sup.7 is hydrogen, lower alkyl or lower alkoxycarbonyl; or PA1 R.sup.3 is hydrogen or lower alkyl; PA1 R.sup.4 is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R.sup.5 where Y is oxygen or sulfur and R.sup.5 is hydrogen, lower alkyl, lower alkoxy or --N(R.sup.6)R.sup.7 where R.sup.6 is hydrogen or lower alkyl and R.sup.7 is hydrogen, lower alkyl or lower alkoxycarbonyl; or PA1 R.sup.3 and R.sup.4 together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by --C(O)R.sup.8 where R.sup.8 is hydrogen, lower alkyl, lower alkoxy or amino;
or a pharmaceutically acceptable salt thereof; are described, inter alia, in co-pending U.S. patent application Ser. No. 07/633,599, filed Dec. 20, 1990, the disclosure of which is incorporated in full herein by reference.
The compounds of formula (I), including their pharmaceutically acceptable salts, and the compositions containing them, inhibit cholesterol synthesis and are therefore useful in treating disease-states characterized by hypercholesterolemia. In particular, compounds of formula (I) inhibit cholesterol synthesis by inhibiting lanosterol 14.alpha.-demethylase, a cytochrome P-450 enzyme. Compounds of formula (I) are also more effective in inhibiting lanosterol 14.alpha.-demethylase than they are in inhibiting other cytochrome P-450 enzymes, for example, the cytochrome P-450 enzymes which contribute to gonadal and adrenal steroidogenesis and cholesterol degradation. Thus, the compounds of formula (I) are useful in treating disease-states characterized by hypercholesterolemia with minimum effect on the physiological functions of key cytochrome P-450 enzymes.